Ephrin Expression and Function in Cancer

McCarron, J; Stringer, Brett W.; Day, Bryan W.; Boyd, Andrew W.

doi:10.2217/fon.09.146

Cited by 19 publications

(25 citation statements)

References 105 publications

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“…Finely coordinated spatial and temporal regulation of Eph receptor and ephrin expression controls many processes that are critical for development and tissue homeostasis, including the formation of tissue boundaries, assembly of intricate neuronal circuits, remodeling of blood vessels, and organ size1,5. Multiple Eph receptors and/or ephrins are also expressed in both cancer cells and the tumor microenvironment, where they influence tumor properties by enabling aberrant cell-cell communication within and between tumor compartments26–32. Mutations dysregulating Eph function likely also play a role in cancer progression.…”

Section: Eph and Ephrin Dysregulation In Cancermentioning

confidence: 99%

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

2010

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The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumor blood vessels, which suggest important roles for their bidirectional signals in multiple aspects of cancer development and progression. Eph gene mutations likely also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth and migration/invasion of cancer cells in culture as well as tumor growth, invasiveness, angiogenesis, and metastasis in vivo. However, Eph signaling activities in cancer appear to be complex, and are characterized by puzzling dichotomies. The Eph receptors nevertheless represent promising new therapeutic targets in cancer.Eph receptors and their ephrin ligands together form an important cell communication system with widespread roles in normal physiology and disease pathogenesis 1 . Links between Eph receptors and cancer date back to the first identified Eph family member 2 . EphA1 was cloned from a carcinoma cell line in a screen for novel oncogenic tyrosine kinases. The novel receptor was found to be upregulated in tumor versus normal tissues and its overexpression caused the oncogenic transformation of NIH3T3 fibroblasts 2,3 . The first Eph receptor-interacting (ephrin) ligand, EPHRIN-A1, was also identified from cancer cells a few years later 4 . The evidence implicating Eph receptors and ephrins in cancer is now extensive, and continues to grow.The activities of the Eph system in cancer are complex, and intriguing in their paradoxical effects. For example, multiple Eph receptors and/or ephrins are present in essentially all types of cancer cells. However, not only increased but also decreased Eph expression has been linked to cancer progression. Consistent with this dichotomy, there is good evidence that Eph receptors and ephrins can both promote and inhibit tumorigenicity. The factors responsible for these divergent activities are only beginning to be uncovered.Following a brief overview of the Eph and ephrin families and their bidirectional signaling mechanisms, the factors that regulate their expression and the remarkable multiplicity of their roles in cancer will be discussed, and the strategies under evaluation to target the Eph system for cancer therapy outlined. Other reviews provide more in depth information on Eph signaling mechanisms in development and adult physiology 1,[5][6][7][8] . Eph and ephrin familiesIn the human genome there are 9 EphA receptors, which promiscuously bind 5 glycosylphosphatidylinositol (GPI)-linked ephrin-A ligands, and 5 EphB receptors, which NIH Public Access Author ManuscriptNat Rev Cancer. Author manuscript; available in PMC 2010 September 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript promiscuously bind 3 transmembrane ephrin-B ligands 5 . Exceptions are the EPHA4 and EPHB2 receptors, which can also bind ephrin-Bs and EPHRIN-A5, respectively, and EPHB4, which preferentially binds only EPHRIN-B2. Eph receptors typically interact with the cell surface...

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Section: Eph and Ephrin Dysregulation In Cancermentioning

confidence: 99%

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

2010

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“…Initial research on ephrin/Eph focused on embryonic tissue patterning and, subsequently, on adult organ pathologies, including malignancies, tissue injury, inflammation, and wound healing (80,112,165,178,222,254,255,260,331,344). In the brain, EphA7, which is present in ependymal cells and astrocytes, induces reverse signaling in progenitor cells and neuroblasts expressing A2, attenuating the formation of neurons in the olfactory bulb (138).…”

Section: Cpc Migration and The Ephrin/eph Receptor Systemmentioning

confidence: 99%

Aging Effects on Cardiac Progenitor Cell Physiology

Rota

Goichberg

Anversa

et al. 2015

Comprehensive Physiology

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Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy.

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“…Ephrin-Eph-R signaling regulates cell differentiation, proliferation, and migration during development (Kullander and Klein, 2002; Pasquale, 2008) and plays a pivotal role in various cancers (Brantley et al, 2002; McCarron et al, 2010). EphrinA1, an angiogenic protein stimulated by pro-inflammatory cytokines, promotes tumorigenesis through interaction with the EphA2-R (Pandey et al, 1995; Cheng et al, 2002; Brantley-Sieders et al, 2004a,b, 2006; Pasquale, 2008; Miao et al, 2009; Beauchamp and Debinski, 2011).…”

Section: Introductionmentioning

confidence: 99%

Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy

et al. 2014

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EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI). The EphA2-receptor (EphA2-R) potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-κB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT) and EphA2-R-mutant (EphA2-R-M) mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2-R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-κB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF-κB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post-MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy.

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Ephrin Expression and Function in Cancer

Cited by 19 publications

References 105 publications

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Eph receptors and ephrins in cancer: bidirectional signalling and beyond

Aging Effects on Cardiac Progenitor Cell Physiology

Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy

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